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Publication Number
US-11459319-B2
Publication Date
2022-10-04
Expiration Date
Abstract
The present invention provides compounds having the general structural formula (I) (I) and pharmaceutically acceptable derivatives thereof, as described generally and in classes and subclasses herein, and additionally provides pharmaceutical compositions thereof, and methods for the use thereof for the treatment of any of a number of conditions or diseases involving fibrosis and proliferation, and where anti-fibrotic or anti-proliferative activity is beneficial.
Core Innovation
The invention relates to compounds represented by Formula (I), or pharmaceutically acceptable salts thereof, wherein X is a triazole optionally substituted with one or more independent R5 substituents, R1 and R2 are each independently lower alkyl, and A is optionally substituted with one or more independent R5 substituents. The structure further defines R3 and R4 as each independently hydrogen or lower alkyl, or R3 with R4, taken together with the carbon atom to which they are attached, form a carbonyl or a 3-10 membered saturated or unsaturated monocyclic or polycyclic ring, optionally substituted with one or more R5 substituents.
R5 is independently hydrogen, halogen, cyano, hydroxy, nitro, —SO2NR6R7, —CONR6R7, NR6R7, haloalkyl, or lower alkyl group, and R6 and R7 are each independently hydrogen or a lower alkyl group. The disclosure includes related compound Forms (II) and (III) with E/Z and stereoisomers and optically pure isomers, together with pharmaceutically acceptable salts and pharmaceutical compositions.
The disclosure relates to cytochrome P450 (CYP, specifically CYP26) inhibitor pharmaceutical compounds and states that inhibition of CYP26 increases all-trans retinoic acid (ATRA) levels. The described therapeutic approach is directed to conditions involving fibrosis and dysproliferation, aligned with anti-fibrotic and anti-dysproliferative or anti-proliferative activity, and includes disease-condition categories spanning organ fibrosis, ischemia-reperfusion injury, stroke/cerebrovascular contexts, inflammatory and skin disorders, and cancer indications.
Claims Coverage
The independent claim set defines a compound class represented by Formula (I) or pharmaceutically acceptable salts thereof, with structural limitations on X, R1 and R2, A, and R3/R4. Overall, there are 8 inventive features covering the Formula (I) scaffold, selected substituent and ring limitations, and methods associated with ATRA level modulation and CYP26 inhibition.
Formula (I) compound definition with substituted triazole and lower alkyl substituents
A compound represented by Formula (I), or a pharmaceutically acceptable salt thereof, wherein X is a triazole optionally substituted with one or more independent R5 substituents; R1 and R2 are each independently lower alkyl; and A is optionally substituted with one or more independent R5 substituents.
R3/R4-defined carbonyl or ring-forming moiety with optional R5 substitution
R3 and R4 are each independently hydrogen or lower alkyl; or R3 with R4, taken together with the carbon atom to which they are attached, form a carbonyl or a 3-10 membered saturated or unsaturated monocyclic or polycyclic ring, wherein said ring is optionally substituted with one or more R5.
Enumerated R5 substituent set and R6/R7 hydrogen or lower alkyl
Each occurrence of R5 is independently hydrogen, halogen, cyano, hydroxy, nitro, —SO2NR6R7, —CONR6R7, NR6R7, haloalkyl, or lower alkyl group; and R6 and R7 are each independently hydrogen or a lower alkyl group.
Specific triazole isomer for X
The compound of Formula (I) is specified such that X is 1,2,4-triazole-1-yl.
Specific lower alkyl selection for R1 and R2
The compound of Formula (I) is specified such that R1 and R2 are both ethyl.
Ring-size constraint for R3 and R4 forming a monocyclic ring
R3 and R4, taken together with the carbon atom to which they are attached, form a five-membered monocyclic ring.
Treatment by modulating ATRA levels through administration
A method for treating or reducing the severity of a disease or condition by modulating ATRA levels through administering a compound of the specified claim or a related pharmaceutical composition to a subject in need.
Method of inhibiting CYP26 by administering a compound
A method of inhibiting CYP26 in a subject by administering a compound of the specified claim or a pharmaceutical composition thereof.
The claim set covers a defined class of substituted triazole Formula (I) compounds, including constraints on R1/R2, A, the R3/R4 ring-forming options, and the enumerated substituent sets for R5 with R6/R7 restricted to hydrogen or lower alkyl. Dependent limitations narrow the structure, including X to 1,2,4-triazole-1-yl, R1/R2 to ethyl, and ring formation to a five-membered monocycle. The disclosure further includes methods for modulating ATRA levels and for inhibiting CYP26 through administration of the claimed compounds or pharmaceutical compositions.
Stated Advantages
Inhibition of CYP26 increases all-trans retinoic acid (ATRA) levels.
CYP26 selectivity.
Anti-fibrotic and anti-dysproliferative or anti-proliferative activity.
The disclosure notes CYP26 inhibition activity using ATRA metabolism/selectivity against CYP enzymes, including CYP3A4 and multiple other P450 enzymes.
Documented Applications
Therapeutic administration to humans and animals.
Pharmaceutical compositions and kit concepts.
Fibrosis and dysproliferative conditions, including vascular healing and cellular proliferation.
Wound healing.
Myocardial ischemia/infarction.
Collateral vessel development.
Conditions associated with vascular occlusion.
Hepatic, lung, renal, and cerebral fibrosis.
Diabetes-related diseases.
Amyotrophic lateral sclerosis.
Muscular dystrophy.
Cancer.
Psoriasis.
Inflammatory skin diseases and inflammatory joint diseases.
Formulations and combination approaches with VEGF/FGF and anticoagulants/antiplatelets.
Conditions involving fibrosis and dysproliferation.
Organ fibrosis.
Ischemia-reperfusion injury.
Stroke/cerebrovascular contexts.
Inflammatory disorders.
Skin disorders.
Cancer indications.
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